The long-term goal of this project is to develop novel ligands for the dopamine transporter (DAT) which will be useful medications in the treatment of cocaine abuse. The successful new compounds are expected to act: a) either as cocaine antagonists by blocking its effects at the DAT but showing no intrinsic activity on their own or b) as cocaine substitutes by acting as DAT inhibitors without, however, many of the deleterious effects of cocaine. A two-pronged approach will be followed. The first of these involves conformationally restricted analogs of GBR12909 a dopamine uptake inhibitor that appears particular promising in preclinical studies in experimental animals and man. The goal will be uncover novel conformation prototypes possessing enhanced properties as anti-cocaine medications. The second approach is based on evidence indicating that the known DAT inhibitors, cocaine, benztropine, GBR 12909 and mazindol interact with the DAT but have non-identical binding domains. This approach involves the development of two sets of chimeric molecules: a) GBR 12909/benztropine; b) GBR 12909/mazindol hybrids. The three dimensional structures of a judiciously chosen group of key new molecules will be studied using NMR spectroscopy and molecular modeling and correlated with their biochemical/pharmacological properties. The new compounds will be tested for their abilities to compete with different radio-ligands at the hDAT, hSERT, hNET, and their ability to inhibit the uptake of dopamine, serotonin, and norepinephrine as well as their abilities to antagonize the effects of cocaine on the DAT. The compounds will be further evaluated in studies that include examination of both unconditioned and conditioned behavior in rats. Initially the effects of drugs in a locomotor activity assay will be used to obtain necessary information on time course, dose range and behavioral and physiological toxicity. Subsequently, the effects of newly synthesized drugs will be examine din well-validated drug discrimination and drug self-administration procedures to evaluate their ability to mimic or to attenuate the discriminative stimulus and reinforcing effects of cocaine. These procedures will also provide important safety information regarding the abuse potential of candidate medications. This integral approach should facilitate rapid identification of effective medications for advanced preclinical and eventually clinical testing.